Skin comprises three primary layers: epidermis, dermis, and hypodermis. In addition, animal skins are often covered with hairs, which are produced by hair follicles structures. FIG. 1 shows a schematic illustration of a section of a skin with a follicle structure 10. As shown, a hair follicle 12 is associated with sebaceous glands 11, which can deposit sebum 13 on the hairs 15. The sebum eventually rises to the skin surface 15 along the hair shaft. Sebaceous glands are also found in non-haired areas (glabrous skin) such as eyelids. In the non-haired areas, the sebum traverses ducts which terminate in sweat pores on the surface of the skin. The sebaceous glands at the rim of the eyelids are called meibomian glands; they secrete sebum into the tears coating the eye, to slow evaporation.
Sebum is made of fat (lipids) and the debris of dead fat-producing cells. In the sebaceous glands, sebum is produced within specialized cells and is released as these cells burst. Sebum protects and waterproofs hair and skin, keeping them from becoming dry, brittle and cracked. It also inhibits the growth of microorganisms on skin. However, excess secretion of sebum may give rise to skin disorders, such as acne and keratosis pilaris. Medications for treating such skin diseases are available. For example, isotretinoin (a vitamin A analog) can significantly reduce the amount of sebum produced by the sebaceous glands and may be used to treat acne. Isotretinoin may be used orally (such as Accutane® from Roche) or topically (such as Isotrex® or Isotrexin® from Stiefel). The precise mechanism of isotretinoin's action is unknown, though its action is thought to be mediated by its effects on cellular transcription.
The compositions of sebum vary from species to species. In humans, the lipid content is as follows: wax monoesters (25%), triglycerides (41%), free fatty acids (16%), and squalenes (12%). See, J. B. Cheng et al., “Mammalian Wax Biosynthesis II: Expression Cloning of Wax Synthase cDNAs Encoding a Member of the Acyltransferase Enzyme Family,” J. Biol. Chem., 2004 Sep. 3; 279(36):37798-37807. Thus, fats and fatty acids are the main components of sebum. Accordingly, manipulating fat production in sebaceous glands may offer an approach to the control of sebum production, and hence a way to treat or prevent skin disorders associated with excess sebum production.
Acyl desaturases are critical enzymes involved in the synthesis of fats or lipids. They catalyze the formation of double bonds in fatty acids. Mammals synthesize at least three fatty acid desaturases having differing chain length specificity that catalyze the formation of double bonds at the 9, 6, and 5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond at the C9-C10 position of saturated fatty acids. The preferred substrates for SCDs are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively. The resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters.
A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). A single SCD gene, SCD1, has been characterized in humans (Brownlie et al. PCT application, WO 01/62954). A second human SCD isoform has recently been identified (PCT application, WO 02/26944). Because this isoform bears little sequence homology to other mouse or rat isoforms, it has been named human SCD5 or hSCD5.
Basic biochemical roles of SCD have been known in rats and mice for some time (Jeffcoat, R. et al., Elsevier Science (1984), Vol. 4, pp. 85-112; de Antueno, R J, Lipids (1993), Vol. 28, No. 4, pp. 285-290). They have also been implicated in human disease processes. For example, abnormal SCD1 activity has been linked to skin disorders. Zheng, et al., Nat. Genet. (1999) 23:268-270, show that rodents lacking a functional SCD gene have reduced sebum production and associated changes in the conditions of their eyes, skin and coat. In addition, Miyazaki, et al., J. Nutr. (2001), Vol. 131, pp 2260-2268, noted that SCD1−/− mice develop cutaneous abnormalities, associated with atrophic sebaceous and meibomian glands. These observations suggest a possibility of treating or preventing skin disorders that are associated with excess sebum productions, such as acne, rosacea, and seborrheic skin, by inhibiting SCD activities.
To date, no small-molecule, drug-like compounds are known that specifically inhibit or modulate SCD activities. Certain long-chain fatty-acid analogs have been found to inhibit SCD activities, presumably by competing with substrates in the active sites of these enzymes. For example, cis-12, trans-10 conjugated linoleic acid can inhibit SCD activity and reduce the abundance of SCD1 mRNA. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, can also inhibit SCD activity, including sterculic acid (8-(2-octylcyclopropenyl)-octanoic acid) and malvalic acid (7-(2-octylcyclopropenyl)heptanoic acid), which are C18 and C16 analogs of sterculoyl and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C10 positions. Other agents that may inhibit SCD include thia-fatty acids, e.g., 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a sulfoxy moiety.
These known modulators of delta-9 desaturase activity are not useful for treating diseases and disorders linked to SCD1 because they are neither useful at reasonable doses, nor specific inhibitors of SCD1. Instead, they demonstrate cross inhibition of other desaturases, in particular the delta-5 and delta-6 desaturases.
The absence of small molecule inhibitors of SCD is a major scientific and medical disappointment because evidence is now compelling that SCD activity is directly implicated in various human disease processes (including skin diseases): See e.g., Attic, A. D. et al., “Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia”, J. Lipid Res. (2002), Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., “Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss”, Science (2002), Vol. 297, No. 5579, pp. 240-3, Ntambi, J. M. et al, “Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity”, Proc. Natl. Acad. Sci. USA. (2002), Vol. 99, No. 7, pp. 11482-6.
As noted above, inhibitors of SCD may be useful in the treatment or prevention of skin disorders such as acne, rosacea, and seborrheic skin. Although other medications for acne are available, there is still a need for therapeutic agents that treat these skin disorders by different mechanisms.